Jeon Young Jin, Youk Eun Soo, Lee Sang Han, Suh Jaehong, Na Yong Joo, Kim Hwan Mook
Department of Pharmacology, Chosun University School of Medicine, 375 Susukdong, Kwangju, Korea.
Toxicol Appl Pharmacol. 2002 Jun 1;181(2):69-78. doi: 10.1006/taap.2002.9389.
Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants and many of their toxic effects, including their immunotoxicities, are mediated by the activation of aryl hydrocarbon receptor (AhR). We previously reported that Aroclor 1254, one of the most widely used PCB mixtures, increased DNA fragmentation in mouse spleen cells, suggesting that apoptosis was correlated with the immunotoxicity of PCB (Yoo et al., Toxicol. Lett. 91, 83-89, 1997). In the present study we investigated the mechanism by which PCB induces apoptosis and the involvement of AhR in the PCB-mediated apoptosis of mouse spleen cells. Aroclor 1254 induced DNA fragmentation without AhR activation, and the apoptosis was unaffected by alpha-naphtoflavone, a well-known antagonist of AhR. Moreover, the PCB congeners (PCB 47, 52, 128, and 153), which have little affinity for AhR, induced DNA fragmentation, whereas congeners (PCB 77, 126, and 169) that have high affinity for AhR did not induce fragmentation. The di-ortho form of PCB (PCB 153) and Aroclor 1254 induced DNA fragmentation in the spleen cells of both AhR knockout mice and Ah low-response mice, whereas the non-ortho form of PCB (PCB 126) did not induce DNA fragmentation. In the light of these findings, it is evident that AhR is not involved in PCB-mediated apoptosis. PCB 153 significantly increased caspase-3 activity in both spleen cells and human leukemia cells, and z-VAD-fmk, a general inhibitor of caspases, prevented PCB-induced DNA fragmentation. Based on our findings, the most likely mechanism that can account for this biological effect involves the induction of caspase-dependent apoptotic cell death.
多氯联苯（PCBs）是普遍存在的环境污染物，它们的许多毒性作用，包括免疫毒性，都是由芳烃受体（AhR）的激活介导的。我们之前报道过，Aroclor 1254是使用最广泛的多氯联苯混合物之一，它会增加小鼠脾细胞中的DNA片段化，这表明细胞凋亡与多氯联苯的免疫毒性相关（Yoo等人，《毒理学快报》91卷，83 - 89页，1997年）。在本研究中，我们调查了多氯联苯诱导细胞凋亡的机制以及AhR在多氯联苯介导的小鼠脾细胞凋亡中的作用。Aroclor 1254在未激活AhR的情况下诱导了DNA片段化，并且细胞凋亡不受AhR的著名拮抗剂α-萘黄酮的影响。此外，对AhR亲和力低的多氯联苯同系物（PCB 47、52、128和153）诱导了DNA片段化，而对AhR亲和力高的同系物（PCB 77、126和169）则未诱导片段化。多氯联苯的邻位二取代形式（PCB 153）和Aroclor 1254在AhR基因敲除小鼠和Ah低反应小鼠的脾细胞中均诱导了DNA片段化，而非邻位形式的多氯联苯（PCB 126）未诱导DNA片段化。根据这些发现，很明显AhR不参与多氯联苯介导的细胞凋亡。PCB 153显著增加了脾细胞和人白血病细胞中的半胱天冬酶-3活性，并且半胱天冬酶的通用抑制剂z-VAD-fmk可阻止多氯联苯诱导的DNA片段化。基于我们的发现，最有可能解释这种生物学效应的机制涉及半胱天冬酶依赖性凋亡性细胞死亡的诱导。
